Several previous studies have shown that .gamma.-aminobutyric acid is a major inhibitory transmitter of the central nervous system as reported, for example, by S. Kranjevic, Physiological Reviews 54, 418-540 (1974) and that disturbance of the excitation and inhibition interplay can lead to diseased states such as Huntington's chorea (The Lancet, Nov. 9, 1974, pp. 1122-1123), Parkinsonism, schizophrenia, epilepsy, depression, hyperkinesis and manic depression disorders, E. Roberts, Biochem. Pharmacol. 23, 2637-2649 (1974). Certain compounds are known to elevate brain levels of .gamma.-aminobutyric acid, for example, n-dipropylacetate (Simler et al., Biochem. Pharm., 22 1701 (1973)) by competitively inhibiting .gamma.-aminobutyric acid transaminase resulting in a reversible effect which lasts for only about 2 hours. Also, 4-aminotetrolic acid (P. M. Beart et al., J. Neurochem. 19 1849 (1972)) is known to be a competitive reversible inhibitor of .gamma.-aminobutyric acid transaminase.
U.S. Pat. Nos. 3,959,356 and 3,960,927 cover respectively acetylenic and olefinic derivatives of amino acids which are irreversible inhibitors of .gamma.-aminobutyric acid transaminase.
The natural product gabaculine or 5-amino-1,3-cyclohexadiene-1-carboxylic acid is known to be a selective irreversible inhibitor of .gamma.-aminobutyric acid transaminase in vitro and in vivo (Kobayashi et al., Tetrahedron letters 1976, 537; R. Rando and F. W. Bangerter, Biochem. Biophys. Res. Comm. 76, 1276 (1977); and J. Am. Chem. Soc. 98, 6762, (1976); Kobayashi et al., FEBS. Lett. 76, 207, (1977); and R. D. Allan et al., Neuroscience Lett. 4, 51 (1977)), gabaculine acting as a substrate for the transaminase. Gabaculine thus avoids the depletion of 4-aminobutyric acid which depletion is connected with central nervous system diseases like Parkinsonism and epilepsy.
It has now been found that compounds of the present invention are irreversible inhibitors of .gamma.-amino butyric acid transaminase of a better efficiency than gabaculine and certain other known irreversible inhibitors of .gamma.-aminobutyric acid transaminase rendering said compounds particularly useful in the treatment of aforesaid diseased states.